Autism is a severe developmental disorder characterized by abnormalities in the manner in which the brain collects and integrates information resulting in abnormal communication and social skills. Currently, there is no known single cause for autism; however, recent investigations suggest that autism has a biological basis and results from a combination of factors including genetic, immunologic, viral or other. Several recent immunogenetic and immunoregulatory findings, in our laboratory and elsewhere, suggest that some cases of autism may result from an autoimmune mechanism. Moreover, autism expresses several disease characteristics as seen in known autoimmune disorders such as multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus. This project will attempt to gain concrete evidence for or against the existence of autoimmune mechanisms in autism. This renewal proposal has four specific aims: (1) a confirmation and expansion of studies of a recent exciting finding that we have made on an association of the extended major histocompatibility complex (MHC) complex and the C4B null (QO) allele with autism. Most autoimmune disorders are associated with the MHC and several autoimmune diseases are associated with null alleles of the C4 complement loci;(2) an investigation of the basis and relevance of abnormal immune regulatory function in autistic children with the results being compared with those from healthy subjects and subjects with idiopathic mental retardation; (3) a study of in vitro antibody production and suppressor T cell regulation; and (4) an exploration of the sera of autistic subjects for specific autoantibodies against the brain-tissue antigens myelin basic protein, serotonin receptor and neuron-axon filament proteins. The proposed studies may firmly establish a biological correlate or marker for autism and, hopefully, lead to eventual therapeutic intervention with immunomodulating agents for this severe disorder.